Erythropoietin, a cytokine made in the kidney, has proven to be effective therapy for anemia in patients with end-stage renal disease. The tissue distribution and regulation of gene expression for erythropoietin and its receptor reveal important insight on erythropoietin induction by hypoxia, on its role in mature red cell production and its activity in non-hematopoietic tissues. Erythropoietin acts primarily to regulate blood hemoglobin through the formation of mature red blood cells and binds to its receptor on the surface of erythroid progenitor cells to promote erythropoiesis by preventing apoptosis and stimulating proliferation and differentiation. Mice that lack erythropoietin or its receptor die in utero from severe anemia. To determine the role of endogenous erythropoietin beyond erythropoiesis, we examined mice with erythropoietin receptor expression restricted to hematopoietic tissue. These animals survived through adulthood with normalized erythroid differentiation and hematocrit, and exhibited no gross morphologic deformation. We observed that these mice are glucose intolerant and exhibit an age dependent obesity with increase in body weight up to twice that of wild type animals at 12 months. The onset of insulin resistance appeared concomitantly with weight gain, principally in white fat mass. These differences could not be attributed to differences in food intake. Indirect calorimetry assay on these mice demonstrated no difference in young mice but a significantly decreased metabolic rate and activity in old, obese mice (18 months), suggesting that reduced activity is not the primary cause of weight gain. We observed erythropoietin receptor expression in white fat and the role of erythropoietin in adipogenesis and the effect of erythropoietin on glucose metabolism in wild type animals are currently under investigation. These observations suggest that erythropoietin may play a role in modulating adipogenesis and glucose metabolism and provide new insight on erythropoietin biology.